Preliminary investigations indicate that glucose-6-phosphate dehydrogenase (G6PD) of normal and G6PD-deficient human red cells is either severely inhibited or functionally inaccessible. The nature of this intracellular impairment is unknown. A series of studies is proposed to elucidate the mechanism of intracellular control of G6PD and the hexose monophosphate shunt (HMS) and to explain discrepancies between levels of G6PD activity in hemolysates and clinical severity among G6PD-deficient subjects. The studies will include determination of HMS function and NADPH/NADP ratios in normal and various G6PD- deficient red cells, under conditions of both rest and oxidative stress. Related biochemical and mathematical genetic studies are proposed that could eliminate several uncertainties in antenatal diagnosis.